This invention relates to organ preservation systems, but specifically to such devices that are used to preserve an organ/biological entity for transplantation or isolated study or evaluation.
The invention allows an organ or a biological entity to be maintained in an active oxygenated state. This in turn greatly increases the viability of the organ while awaiting a host. It will also be used to study individual organ physiology for pharmaceuticals or any homeostatic or dynamic physiological state in which substances, chemicals, or nutrients are measured from the vascular connections.
Currently, transplant organs are stored at low temperatures to slow metabolism and thus increase the survival time of the organ and the probability of the organ being successfully transplanted. These organs still have a limited time of survival as they are in a hypoxic or low oxygen state since oxygen cannot be supplied to the tissues in adequate amounts. The survival of any organ will depend on how soon it depletes its oxygen and finally its energy stores to where even anaerobic metabolism is not possible. Organ preservation currently consists of cooling the organ to about four degrees centigrade and using preservation solutions such as UW (University of Wisconsin) or Euro-Collis (EC) solution. These still only allow limited time before the tissues are incapable of returning to an aerobic state when transplanted. Ploeg (Transplantation Feb 90) demonstrated a 24 hour median preservation time with maximum preservation time of 48 hours in a series of 257 kidney transplant patients. Stratta (transplantation Sep 90) demonstrated only a mean preservation time of 5.2 hours and 12.8 hours using EC and UW respectively in 308 liver transplant cases. One concern following a prolonged anaerobic tissue state is reperfusion injury where oxygen radicals and superoxides are formed when circulation is restored in the organ after transplantation. These radicals and superoxides in turn destroy cellular components and compromise the success of the organ surviving. This invention facilitates the organ/biological entity to remain in aerobic metabolism thus preventing reperfusion and increasing transplantation success.
The theory of using hyperbaric oxygen for hypoxic wounds has been in existence for over 30 years. Oxygen is breathed at greater than one atmosphere absolute or ATA (usually between 2 and 3 ATA). This takes advantage of normal physics by increasing the partial pressure of oxygen and thus driving oxygen into solution within the plasma other body fluids. This increases the amount of oxygen available to tissues and cells. The ability of using 100% oxygen at 3 ATA to sustain life in a bloodless animal was demonstrated in 1960 by Borema (J. Cardiovascular Surg. 1:133-146, 1960). This concept of is extended by this invention by establishing a means by which to oxygenate an isolated organ/biological entity sufficiently to meet the oxygen demand of the organ/biological entity. This is the critical novelty that separates this invention from the prior art.
U.S. Pat. Nos. 3,067,646 and 3,772,153 to De Roissart uses a complicated system to preserve the organ under hyperbaric conditions of 2 to 15 bars pressure, about 2 to 15 ATA. The system interconnects four separately pressurized containers and uses a mixture of an inert gas (preferably helium) and no more than 10% oxygen to both pressurize the system and to oxygenate the prefusate via agitation. There are many disadvantages in de Roissait""s system that my invention overcomes. First my invention is a single pressurized unit, thus simpler in design and control. Second, de Roissart takes considerable time explaining how to prevent gas embolus from blocking the organ""s vessels. If this were to occur, the organ would have a higher risk of failure. An embolus may occur in his system due to the inert gas coming out of solution and form bubbles within the blood vessels when the system is depressurized. This is similar to bubbles coming out of solution when a soda is opened. My system is pressurized with about 100% oxygen that is metabolically active unlike any inert gas and does not come out of solution when the system is depressurized for organ transplantation. Third, de Roissart""s system relies on oxygenation of the perfusate in a nutrient fluid container. This occurs at the surface interface between the perfusate and pressurized gas mixture. This follows standard gas diffusion laws. Even though he has an agitator, this is a very inefficient means of drifting the gas into solution because of the relatively small surface area between the gas and fluid. My system overcomes this by actively using a high surface area oxygenator within the pressurized system. This dramatically increases the relative surface area between the fluid and oxygen used in my invention, thus quickly oxygenating the perfusate. My system, preferably using a minimum of 3 ATA, makes the oxygen readily available to the organ tissue at a partial pressure that is at least as high as within the lining body. This, is turn, decreases the likelihood of reperfusion injury at the time of transplantation. In order for de Roissart""s system to accommodate the same tissue levels, the pressure of his system would need to be near 30 bars, twice his upper parameter! Although my system can store organs at low temperatures, it can also supply the organ with sufficient oxygen to continue normal metabolism at normal body temperature. This is not possible with de Roissart""s system.
U.S. Pat. No. 4,837,390 to Reneau describes a system in which the organ is immersed in a bath of perfusate and stored in an organ preservation vessel within a hyperbaric chamber. The pressure can be up to 15 bars. Oxygenation of the perfusate is at ambient pressure (1 ATA) within a fluid reservoir using only the surface interface between the perfusate and pressurized gas. The gas is not specified, but inferred to be oxygen. My invention improves dramatically upon this. First my system overcomes this by actively using a high surface area oxygenator within the pressurized chamber vessel. This dramatically increases the relative surface area between the fluid and oxygen used in my invention, thus quickly oxygenating the perfusate. Second, the organ is actively perfused in my invention versus merely immersed in the perfusate. This is critical to the survivability of the organ as immersion alone only allows passive diffusion of oxygen and nutrients from the surface of the organ and little use of the organs vasculature. My invention actively perfuses the organ within the hyperbaric environment by pumping the perfusate from the pump and into the arterial vasculature and microvasculature. The perfusate is removed from the organ""s venous vasculature via the conduit that passes through the hyperbaric chamber. By such an arrangement, the system uses the pressure within the chamber to actively transport the perfusate out of the organ and chamber because of the pressure differential. This mimics the pressure differential and thus flow of blood in a living mammal.
U.S. Pat. Nos. 4,186,565 to Toledo-Pereyra, 5,157,930 to McGhee, and 3,753,865 to Belzer establish a closed organ perfusing system that uses a pump to circulate the perfusate, but operates at ambient pressure. U.S. Pat. No. 5,965,433 to Gardetto also works within an ambient pressure environment utilizing dual pumps that push the perfusate into the organ. McGhee""s system does not have a high surface area oxygenator to increase the oxygen in solution. The perfusate is returned by pumping drained perfusate from an open reservoir. In all of these systems, by only pushing the perfusate in an isobaric system, rather than pushing from the arterial side and pulling from the venous side as done in my invention, using pressure differentials, there is an increased risk of cellular edema and damage to the organ. In addition, the oxygenation and the storage of the organ is not in a high enough gas pressure and therefore does not take advantage of hyperbaric gas laws to increase oxygen into the perfusate.
U.S. Pat. No. 5,356,771 to O""Dell uses pressurized oxygen to drive an oxygen permeable membrane to pump perfusate from container one into the arterial side of an organ within another container. There is a free flow from container two back to container one. The perfusate is oxygenated from the relatively small surface area membrane. Although O""Dell mentions this as a hyperbaric perfusion, the hyperbaric forces driving oxygen into the perfusate are only present when the pressurized oxygen pushes the membrane. This is a momentary condition and only a pressure of 20 mmHg. This is near ambient pressure compared to a driving force of about 2280 mmHg in my invention. Furthermore, the pressure returns to ambient in order to complete the pumping cycle, thus the true hyperbaric forces are minimal. Again, my invention also uses a high surface area oxygenating component.
U.S. Pat. No. 5,494,822 to Sadri offers a system that controls perfusion pressure or flow rate by an intricate combination of pumps and computer controls. A unique aspect is a pump from the venous side that effectively pulls the perfusate from the organ from a mechanical means versus the gas pressure differential used in my invention. The critical difference in Sadri""s system is that the oxygenation and the storage of the organ is not in a high enough gas pressure and therefore does not take advantage of hyperbaric gas laws to increase oxygen in the perfusate as happens with my invention.
The above organ preservation systems suffer from a number of disadvantages:
(a) They do not combine a high oxygen (up to 100%) hyperbaric environment with a large surface area oxygenator, thus taking advantage of physical gas laws that drive high amounts of oxygen into solution, in this case the perfusate.
(b) They do not achieve a high enough oxygen level in the perfusate to sustain normal metabolism at the normal body temperature range.
(c) They do not achieve a high enough oxygen level for a sustained period of time to avoid or minimize reperfusion injury when the organ is transplanted into the receiving host.
(d) They consist of relatively elaborate system of tubes or reservoirs that hinder the ability to remove waste products from the perfusate.
(e) They generally are manufactured with cumbersome refrigeration systems that add to the weight and bulk of the systems.
(f) They generally do not allow for the isolation study of an organ or biological entity
Accordingly, several objects and advantages of my invention are:
(a) to provide a method in which a perfusate is oxygenated by a large surface area oxygenator within a high oxygen hyperbaric environment;
(b) to provide a method in which a perfusate is oxygenated by a large surface area oxygenator within a high oxygen hyperbaric environment sufficient enough to raise the oxygen content of the perfusate to at least 4.5 volume percent oxygen;
(c) to provide a method by which the above perfusate is delivered to an organ/biological so that said organ/biological entity can extract oxygen and nutrients;
(d) to provide a method by which the above perfusate is delivered to an organ/biological so that said organ/biological entity can extract oxygen and nutrients to remain viable from a temperature range of less than 0 to more than 40 degrees centigrade;
(e) to provide a method by which the above perfusate is delivered to an organ/biological so that said organ/biological entity can extract oxygen and nutrients to remain viable for at least 24 hours;
(f) to provide a method by which the above perfusate is delivered to an organ/biological so that said organ/biological entity such that cellular edema is minimal or non-existent;
(g) to provide a method by which said organ/biological entity""s waste products are easily removed from the perfusate;
(h) to provide a method by which the perfusate can easily be sampled for tests or evaluations including, but not limited to biochemical, microbiological enzymatic, electolyte, or nutritional;
(i) to provide a method by which the above perfusate is delivered to an organ/biological so that said organ/biological entity can extract oxygen and nutrients to remain viable for transplantation with minimal reperfusion injury to the organ or entity;
(j) to provide a method by which the above perfusate is delivered to an organ/biological so that said organ/biological entity can extract oxygen and nutrients to remain viable during medical or surgical treatment, then be available for retransplantation into the original host.
Further objects and advantages of my invention will become apparent from a consideration of the drawings and ensuing description.